Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study

Daniel Burns, Ezequiel Anokian, Edward J. Saunders, Robert G. Bristow, Michael Fraser, Jüri Reimand, Thorsten Schlomm, Guido Sauter, Benedikt Brors, Jan Korbel, Joachim Weischenfeldt, Sebastian M. Waszak, Niall M. Corcoran, Chol-Hee Jung, Bernard J. Pope, Chris M. Hovens, Géraldine Cancel-Tassin, Olivier Cussenot, Massimo Loda, Chris SanderVanessa M. Hayes, Karina Dalsgaard Sorensen, Yong-Jie Lu, Freddie C. Hamdy, Christopher S. Foster, Vincent Gnanapragasam, Adam Butler, Andy G. Lynch, Charlie E. Massie, CR-UK/Prostate Cancer UK, ICGC, The PPCG, Dan J. Woodcock, Colin S. Cooper, David C. Wedge, Daniel S. Brewer, Zsofia Kote-Jarai, Rosalind A. Eeles

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Abstract

Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. 

Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa, and understand the genetic factors associated with such progression. 

Design, Setting and Participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG consortium) from UK, Canada, Germany, Australia and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA). 
Outcome Measurements and Statistical analysis: 15,822 rare (MAF<1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene-sets. Models were tested for robustness using bootstrap resampling. 

Results: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in “Hallmark” gene-sets were consistently associated with altered time to BCR. Three gene-sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB and Hypoxia, the latter of which was validated in the independent TCGA dataset. 

Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. 

Patient summary: PrCa patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify which patients might need additional treatments earlier.
Original languageEnglish
JournalEuropean Urology
Early online date31 May 2022
DOIs
Publication statusE-pub ahead of print - 31 May 2022

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